EP1873152B1 - Novel purification process of moxonidine - Google Patents
Novel purification process of moxonidine Download PDFInfo
- Publication number
- EP1873152B1 EP1873152B1 EP06013134A EP06013134A EP1873152B1 EP 1873152 B1 EP1873152 B1 EP 1873152B1 EP 06013134 A EP06013134 A EP 06013134A EP 06013134 A EP06013134 A EP 06013134A EP 1873152 B1 EP1873152 B1 EP 1873152B1
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- EP
- European Patent Office
- Prior art keywords
- moxonidine
- solvents
- dmso
- solvent
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- WPNJAUFVNXKLIM-UHFFFAOYSA-N Cc(nc1Cl)nc(OC)c1NC1=NCCN1 Chemical compound Cc(nc1Cl)nc(OC)c1NC1=NCCN1 WPNJAUFVNXKLIM-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention relates to a novel purification process of the drug Moxonidine.
- Moxonidine (4-chloro-5-(imidazoline-2-ylamino)-6-methoxy-2-methylpyrimidine), has the structural formula (I) below and is used as an antihypertensive drug.
- Moxonidine was approved for use in Germany in 1991 and is currently commercially available in Europe, e.g., in Germany, Austria and in the UK.
- U.S. patent No. 4,323,570 (hereinafter the '570 patent) describes a method of preparing Moxonidine (I) by reacting 4,6-dichloro-2-methyl-5-(1-acetyl-2-imidazolin-2-yl)-aminopyrimidine (hereinafter DMAIA) with about 2 equivalents of sodium methoxide in methanol under reflux. It is stated in example 3 of the '570 patent that Moxonidine is obtained by crystallization from nitromethane having a melting point of 217-219°C. The hydrochloride salt of Moxonidine is described in example 25, having a melting point of 189°C.
- Nitromethane the solvent from which moxonidine is recrystallized, is a hazardous and explosive solvent in addition to being toxic (the allowed limit of nitromethane in human drugs, according to ICH guideline is merely 50 ppm). It is incompatible with many commonly used industrial reagents e.g., amines, strong acids and strong bases. Therefore, the crystallization from nitromethane is not suitable for industrial implementation due to its hazardous nature. Its toxicity renders it not suitable for use in human drugs. Thus there is a need in the art for an alternative purification process of Moxonidine using safer and more environmentally friendly solvents.
- the inventors of the present invention have surprisingly discovered that not only it is possible to purify crude Moxonidine from high boiling point polar solvents and to obtain the crystallized Moxonidine in high quality and yield, but also the final product is obtained containing a negligible amount of the solvent.
- the process for preparing the purified Moxonidine comprises:
- the purified Moxonidine is obtained as described herein having residual solvent of less than 1000 ppm, preferably of less than 500 ppm and more preferably of less than 250 ppm.
- the purified Moxonidine is obtained as described herein having a purity of at least 98%, preferably in a purity equal to or greater than 99.5%, and more preferably in a purity equal to or greater than 99.8%.
- the crystalline Moxonidine form I produces a unique X-ray powder diffraction pattern ( figure 1 ).
- the strong diffraction peaks at 12.1, 13.4, 18.4, 22.6, 23.7, 25.5, 27.1 and 28.2 ⁇ 0.2 degrees 2 ⁇ are most characteristic of this form.
- the characteristic TGA curve of the crystalline Moxonidine form I is depicted in figure 3 .
- ICH class 3 solvents or selected class 2 solvents which are safer and more environmentally friendly than nitromethane, may be used instead for preparing highly pure Moxonidine.
- the inventors of the present invention have used the guidance " Q3C: Residual Solvents" published by the "International Conference on Harmonization of Technical Requirements of Registration of Pharmaceuticals for Human Use (ICH)". A copy of this guidance can be found in the US Federal register Volume 62, No.
- polar solvents have high boiling points, e.g., the boiling point of DMSO is 189°C, that of DMA is 165°C and for NMP the value is 202°C. Therefore it is usually difficult to eliminate the solvent from the final product, which tends to contain substantial amount of the solvent.
- the inventors of the present invention have surprisingly discovered that not only it is possible to purify crude Moxonidine from high boiling point polar solvents and to obtain the crystallized Moxonidine in high quality and yield, but also the final product is obtained containing a negligible amount of the solvent.
- the inventors of the present invention have surprisingly found that small amounts of acid, such as acetic acid can reduce significantly the levels of compound II in Moxonidine.
- the present invention provides a process for preparing the crystalline Moxonidine by crystallization from the above solvents for which the permitted level in human drugs is 500 ppm or higher.
- high boiling point polar solvents e.g., dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP), or a mixture thereof are most suitable for purifying Moxonidine because while crystallizing from these solvents, the content of the impurity compound (III) is significantly reduced.
- DMSO dimethyl sulfoxide
- DMF N,N-dimethylformamide
- DMA N,N-dimethylacetamide
- NMP N-methyl-2-pyrrolidone
- Moxonodine may be crystallized from a mixture of a high boiling point solvent e.g., dimethyl sulfoxide (DMSO) and an acid, wherein a suitable acid can be either an inorganic acid or an organic acid, e.g., formic acid, acetic acid or propionic acid.
- a high boiling point solvent e.g., dimethyl sulfoxide (DMSO)
- a suitable acid can be either an inorganic acid or an organic acid, e.g., formic acid, acetic acid or propionic acid.
- the purified Moxonidine is obtained as described herein having residual solvent of less than 1000 ppm, preferably of less than 500 ppm and more preferably of less than 250 ppm.
- the purified Moxonidine is obtained as described herein having a purity of at least 98%, preferably in a purity equal to or greater than 99.5%, and more preferably in a purity equal to or greater than 99.8%.
- the crystalline Moxonidine form I produces a unique X-ray powder diffraction pattern ( figure 1 and table 1).
- the strong diffraction peaks at 12.1, 13.4, 18.4, 22.6, 23.7, 25.5, 27.1 and 28.2 ⁇ 0.2 degrees 2 ⁇ are most characteristic of this form.
- Table 1 - Crystalline Moxonidine form I - X-ray powder diffraction peak positions and intensities Peak position 2 ⁇ degrees Relative intensity I/I 0 Peak position 2 ⁇ degrees Relative intensity I/I 0 8.8 4.6 24.4 7.0 12.1 82.4 25.5 100.0 13.4 49.6 26.1 9.8 17.0 6.9 26.6 5.8 17.4 3.4 27.1 21.8 17.6 4.0 28.2 17.5 18.4 24.9 28.8 4.7 19.2 0.9 29.3 1.9 20.3 1.3 30.1 2.4 22.6 56.7 31.7 1.4 23.1 5.9 33.6 3.2 23.7 30.3 34.4 3.0
- the characteristic DSC curve of the crystalline Moxonidine form I which contains an exothermic peak at about 227°C, is depicted in figure 2 .
- the characteristic TGA curve of the crystalline Moxonidine form I is depicted in figure 3 .
- Example 10-12 Crystallization of crude Moxonidine from mixtures of high boiling point solvent and acetic acid
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Solid-Sorbent Or Filter-Aiding Compositions (AREA)
- Steroid Compounds (AREA)
- Treatment Of Liquids With Adsorbents In General (AREA)
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT06013134T ATE411310T1 (de) | 2006-06-26 | 2006-06-26 | Reinigungsverfahren von moxonidine |
DE602006003204T DE602006003204D1 (de) | 2006-06-26 | 2006-06-26 | Reinigungsverfahren von Moxonidine |
EP06013134A EP1873152B1 (en) | 2006-06-26 | 2006-06-26 | Novel purification process of moxonidine |
DK06013134T DK1873152T3 (da) | 2006-06-26 | 2006-06-26 | Hidtil ukendt fremgangsmåde til oprensning af Moxonidin |
ES06013134T ES2315967T3 (es) | 2006-06-26 | 2006-06-26 | Nuevo procedimiento de purificacion de moxonidina. |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP06013134A EP1873152B1 (en) | 2006-06-26 | 2006-06-26 | Novel purification process of moxonidine |
Publications (2)
Publication Number | Publication Date |
---|---|
EP1873152A1 EP1873152A1 (en) | 2008-01-02 |
EP1873152B1 true EP1873152B1 (en) | 2008-10-15 |
Family
ID=36779698
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP06013134A Not-in-force EP1873152B1 (en) | 2006-06-26 | 2006-06-26 | Novel purification process of moxonidine |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1873152B1 (da) |
AT (1) | ATE411310T1 (da) |
DE (1) | DE602006003204D1 (da) |
DK (1) | DK1873152T3 (da) |
ES (1) | ES2315967T3 (da) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2054391A4 (en) * | 2006-08-17 | 2009-08-26 | Chemagis Ltd | A SINGLE TAUTOMER-CONTAINING CRYSTALLINE MOXONIDINE AND METHOD FOR THE PRODUCTION THEREOF |
DE102012215896A1 (de) * | 2012-09-07 | 2014-03-13 | Wörwag Pharma GmbH & Co.KG | Moxonidinsynthese mit Hilfe organischer Basen |
EP2765131B1 (en) | 2013-02-08 | 2016-11-23 | Arevipharma GmbH | Process for the production of Moxonidine |
EP2829540A1 (en) * | 2013-07-26 | 2015-01-28 | Abbott Healthcare Products B.V. | Synthesis of substituted aminopyridines |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4323570A (en) * | 1978-11-15 | 1982-04-06 | Beiersdorf Aktiengesellschaft | Substituted aminopyrimidines |
-
2006
- 2006-06-26 EP EP06013134A patent/EP1873152B1/en not_active Not-in-force
- 2006-06-26 AT AT06013134T patent/ATE411310T1/de active
- 2006-06-26 ES ES06013134T patent/ES2315967T3/es active Active
- 2006-06-26 DK DK06013134T patent/DK1873152T3/da active
- 2006-06-26 DE DE602006003204T patent/DE602006003204D1/de active Active
Also Published As
Publication number | Publication date |
---|---|
ES2315967T3 (es) | 2009-04-01 |
ATE411310T1 (de) | 2008-10-15 |
DK1873152T3 (da) | 2009-02-09 |
DE602006003204D1 (de) | 2008-11-27 |
EP1873152A1 (en) | 2008-01-02 |
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